Ischemic heart disease continues to be a significant medical problem and approaches other than coronary artery revascularization have had no long term success to improve myocardial perfusion. Hyperthyroidism increases coronary perfusion and enhances cardiac capillary density but these beneficial vascular effects are accompanied by undesirable cardiac changes like increases in heart rate and cardiac O2 consumption. It is currently unclear if increasing the expression of thyroid hormone receptor (TR) isoforms TR1 or TR2 only in vascular endothelial cells (ECs) can result in beneficial vascular effects in the absence of undesirable cardiac or systemic changes. In addition the detailed mechanisms by which TR isoforms exert their effects in ECs are largely unexplored. We generated mice with EC specific expression or deletion of TR1 and TR2 to explore effects on vascular function with a focus on coronary perfusion and cardiac capillary density. In Aim I we explore if changes in TR1 or TR2 expression in ECs effects vascular function especially coronary perfusion and coronary artery contraction and relaxation. In addition we identify mechanisms which mediate these changes. Preliminary results show that increased expression of TR11 in ECs leads to a marked increase in coronary perfusion in the absence of undesirable effects like increases in heart rate, oxygen consumption, or a significant decrease in systemic vascular resistance. In Aim II we determine the effects of EC-based TR1 and TR2 expression or deletion on cardiac capillary density. Our preliminary data show that changes of TR2 expression in ECs exerts selective effects markedly increasing cardiac capillary density with no effect by TR1. In Aim III we determine if increasing TR1 or TR2 expression in ECs and restoring ischemia reperfusion (I/R) mediated decreases in TR levels ameliorates I/R mediated cardiac injury. Preliminary results show that exposing hearts or ECs to I/R like conditions significantly lowers EC TR levels. In addition we find that increasing TR expression in ECs ameliorates I/R mediated injury and decreases infarct size under in vivo conditions. The studies may lead to novel approaches to improve coronary perfusion and increase substrate exchange by increasing cardiac capillary density in the absence of undesirable effects. In addition new knowledge related to TR action in ECs will be obtained. POTENTIAL IMPACT ON VETERANS HEALTH CARE: Ischemic heart disease significantly contributes to morbidity and mortality in the veteran patient population. The "preclinical" research of this proposal demonstrates significant improvement in cardiac microcirculatory function and decreased myocardial infarct size by expression of thyroid hormone receptors in vascular endothelial cells. These findings may lead to clinical translation in future approaches. PUBLIC HEALTH RELEVANCE: Decreased perfusion of the heart presents a significant medical problem. New approaches to increase cardiac perfusion and the density of blood vessels in heart muscle may significantly improve the outcome of myocardial infarcts. Increasing the expression of thyroid hormone receptors in endothelial cells may lead to an increase in coronary perfusion and have beneficial effects for ischemic heart disease.